Gene Tx: Temporary Boost in Congenital Blindness

Leber's amaurosis responds to high-dose gene therapy, but not permanently.

Action Points

Gene therapy for the treatment of Leber's congenital amaurosis led to modest improvements in retinal sensitivity for up to 3 years, but those improvements were not sustainable long-term.

Note that an accompanying editorial suggested looking to studies in mice and dogs for finding an effective treatment for LCA.

Gene therapy for the treatment of a congenital disease causing blindness in children led to modest improvements in retinal sensitivity for up to 3 years, but those improvements were not sustainable long-term, according to two small studies.

In a phase I-II open label trial to treat Leber's congenital amaurosis (LCA) in 12 participants, James W.B. Bainbridge, MB BChir, PhD, of the UCL Institute of Ophthalmology in London, and colleagues reported descriptive improvements in retinal sensitivity in participants receiving a higher dose of gene therapy for RPE65 compared with those receiving a lower dose.

Study participants were ages 6 to 23 and had been diagnosed with "early-onset severe retinal dystrophy caused by mutations in RPE65."

They were treated with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector with the RPE65 DNA. Participant received treatment in the eye with the worst vision, with the other acting as a control.

Out of 12 participants, the first four received a lower dose (1x1011), while the last eight received a higher dose (1x1012).

To test the species-specific difference in the treatment, researchers also performed the same study in dogs with naturally occurring RPE65 deficiencies. The messenger RNA in a human eye was 2.5 times higher than in a dog eye (P=0.02), meaning that dogs required a lower amount of RPE65 protein. Indeed, dogs given the lower dose of the treatment had better vision than untreated dogs (P=0.02 by Student's t-test), but the authors noted improvement was strongly correlated with the vector dose (R=0.58, P<0.001).

The majority of improvements were reported by participants in the high-dose group, with only one participant in the low-dose group experiencing improvements in retinal sensitivity for dark-adapted and microperimetry, as well as night vision.

Six participants reported improvements in retinal sensitivity on dark-adapted perimetry, though improvements were limited during the first 4 months after treatment. Five reported improvements in microperimetry.

Five participants also experienced "subjective improvements" in night vision, with three out of five also claiming better "vision-guided ambulatory navigation."

Only two patients had substantial improvements in rod sensitivity 12 months after treatment, while others reported "modest improvements." No participants saw improvement in retinal function, and three actually saw a decline in visual acuity. Two out of three of these reported "subjective deterioration of vision."

As for adverse events, five out of the eight high-dose patients experienced intraocular inflammation or immune responses. One had a reaction to the treatment, and developed "focal pigmentary changes at the macula and a persistent reduction in visual acuity by 15 letters on the ETDRS chart." Two participants had "asymptomatic episodes of posterior intraocular inflammation."

Six out of 10 patients (all four in the low-dose group and six in the high-dose group) had a sustained reduction in macular thickness, usually evident within 3 months of the treatment.

"The systemic adverse events we observed included those known to be associated with oral glucosteroids," the authors wrote.

The authors concluded that gene therapy with rAAV2/2 RPE65 vector did improve retinal sensitivity, but the improvements were modest and temporary.

"Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect," they wrote.

More Efficient RPE65 Delivery

In an accompanying editorial, Alan F. Wright, MB ChB, PhD, of the University of Edinburgh, suggested looking to studies in mice and dogs may hold the key for finding an effective treatment for LCA.

"Extensive preliminary work with the use of mouse and dog models showed that, as long as gene replacement occurs at an early enough stage of the disease, stable and substantial rod and cone vision can be achieved," he wrote.

He notes that dogs treated early continue to achieve good results as much as 7 years after receiving treatment, and suggests that a more efficient RPE65 delivery is needed to treat the disease in humans.

"The use of a lentiviral vector or one of the newer rAAV vectors [or eventually] the clinically routine intravitreal delivery route would be ideal," Wright concluded.

U.S. Study

Patients were diagnosed with LCA and mutations in RPE65 treated with similar gene therapy (AAV2-RPE65). One patient had increased visual sensitivity from 6 months to 3 years after treatment, while the second patient experienced the same at 6 months, before peaking 1 to 3 years after treatment. The third patient had a response 1 year after treatment, before declining.

After 3 years, all three patients experienced a decline in visual sensitivity and a corresponding thinning in the outer nuclear layer of the eye, the authors reported.

"There were fast and slow phases of improvement in vision, as well as a subsequent decline, all overlaid on a progressive, degenerative loss of photoreceptor cells," they wrote. They speculated the continued loss of vision, even after treatment, may be due to degeneration in untreated cells "in a preapoptic cellular stress state."

Jacobson and colleagues suggested early diagnosis is critical to the treatment of LCA, and recommended a decision tree, with disease staging performed using optical coherence tomography to calculate a patient's thickness of the photoreceptor layer and classify a patient's condition as mild, moderate, or severe.

However, both Jacobson and Bainbridge noted that disease severity appeared to be unrelated to age, though the reason why was unclear.

Jacobson's group examined participants ages 23, 21, and 16 at the start of the study, while Bainbridge's team saw the greatest improvements in participants ages 17, 18 and 23.

"Improvements in retinal sensitivity were of lower magnitude in younger participants who had the greatest preservation of retinal structure," Bainbridge and colleagues noted.

Jacobson and colleagues pointed out that "the loss of visual function at later times after treatment is in keeping with progression of the degenerative process. Our observation that the late decrease in visual sensitivity was greater than would be expected, given the thickness of the outer nuclear layer, suggests that the visual cycle may no longer be functioning at the same level as at earlier time points."

The study by Bainbridge's group was supported by the NIHR Biomedical Research Centre at UCL, the Institute of Ophthalmology, the UK Department of Health, RP Fighting Blindness, the Special Trustees of Moorfields Eye Hospital, the Sir Jules Thorn Charitable Trust, the Wellcome Trust, the European Union, the Medical Research Council, Foundation Fighting Blindness, Fight for Sight, the Biotechnology and Biological Sciences Research Council, Research to Prevent Blindness, the Ulverscroft Foundation, the Myers-Dunlap Endowment for Canine Health, and the Hal and Jean Glassen Memorial Foundation.

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